From Environment to Genome and Back : a Lesson from HFE Mutations

The environment and the human genome are closely entangled and many genetic variations that occur in human populations are the result of adaptive selection to ancestral environmental (mainly dietary) conditions. However, the selected mutations may become maladaptive when environmental conditions change, thus becoming candidates for diseases. Hereditary hemochromatosis (HH) is a potentially lethal disease leading to iron accumulation mostly due to mutations in the HFE gene. Indeed, homozygosity for the C282Y HFE mutation is associated with the primary iron overload phenotype. However, both penetrance of the C282Y variant and the clinical manifestation of the disease are extremely variable, suggesting that other genetic, epigenetic and environmental factors play a role in the development of HH, as well as, and in its progression to end-stage liver diseases. Alcohol consumption and dietary habits may impact on the phenotypic expression of HFE-related hemochromatosis. Indeed, dietary components and bioactive molecules can affect iron status both directly by modulating its absorption during digestion and indirectly by the epigenetic modification of genes involved in its uptake, storage and recycling. Thus, the premise of this review is to discuss how environmental pressures led to the selection of HFE mutations and whether nutritional and lifestyle interventions may exert beneficial effects on HH outcomes and comorbidities

Nutrition and genetics in NAFLD : The perfect binomium

Nonalcoholic fatty liver disease (NAFLD) represents a global healthcare burden since it is epidemiologically related to obesity, type 2 diabetes (T2D) and Metabolic Syndrome (MetS). It embraces a wide spectrum of hepatic injuries, which include simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The susceptibility to develop NAFLD is highly variable and it is influenced by several cues including environmental (i.e., dietary habits and physical activity) and inherited (i.e., genetic/epigenetic) risk factors. Nonetheless, even intestinal microbiota and its by-products play a crucial role in NAFLD pathophysiology. The interaction of dietary exposure with the genome is referred to as \u2018nutritional genomics,\u2019 which encompasses both \u2018nutrigenetics\u2019 and \u2018nutriepigenomics.\u2019 It is focused on revealing the biological mechanisms that entail both the acute and persistent genome-nutrient interactions that influence health and it may represent a promising field of study to improve both clinical and health nutrition practices. Thus, the premise of this review is to discuss the relevance of personalized nutritional advices as a novel therapeutic approach in NAFLD tailored management

Self-adhesive electrode applied to ZnO nanorod-based piezoelectric nanogenerators

ZnO nanorod-based piezoelectric devices have gained wide attention in energy harvesting systems as they can be processed at low temperatures onto flexible plastic substrates, giving a good potential for low cost. However, the vacuum-evaporated, precious metal contacts remain a high-cost element of the devices. This paper discusses the use of transparent conductive adhesives (TCAs) as an alternative top contact that is free from both vacuum-evaporation and precious metals. TCA films of various thicknesses were tape-cast onto nickel microgrid on PET substrates and adhered using low-pressure cold-lamination to bond the adhesive component of the TCA to piezoelectric generators with the final device structure of PET/ITO/ZnO-seed/ZnO-nanorods/CuSCN/PEDOT:PSS/TCA. The piezoelectric performances of the devices were compared by measuring output voltage in open-circuit and maximum power output across a range of resistive loads. The voltage output was observed to rise with increasing TCA thickness, reaching a maximum value of 0.72 V generated with 110 µm of TCA as top contact. However, the higher resistance due to increased TCA thickness led to decreased power output; a maximum calculated power of 0.25 μW was obtained from the device with the thinnest TCA layer of 22 µm. Finally, the performance of piezoelectric nanogenerators with TCA contacts were compared to a control device with an evaporated gold contact

High resolution pixel detectors for e+e- linear colliders

The physics goals at the future e+e- linear collider require high performance vertexing and impact parameter resolution. Two possible technologies for the vertex detector of an experimental apparatus are outlined in the paper: an evolution of the Hybrid Pixel Sensors already used in high energy physics experiments and a new detector concept based on the monolithic CMOS sensors.Comment: 8 pages, to appear on the Proceedings of the International Workshop on Linear Colliders LCWS99, Sitges (Spain), April 28 - May 5, 199

Quantum Correlations in the Minimal Scenario

In the minimal scenario of quantum correlations, two parties can choose from two observables with two possible outcomes each. Probabilities are specified by four marginals and four correlations. The resulting four-dimensional convex body of correlations, denoted $\mathcal{Q}$, is fundamental for quantum information theory. It is here studied through the lens of convex algebraic geometry. We review and systematize what is known and add many details, visualizations, and complete proofs. A new result is that $\mathcal{Q}$ is isomorphic to its polar dual. The boundary of $\mathcal{Q}$ consists of three-dimensional faces isomorphic to elliptopes and sextic algebraic manifolds of exposed extreme points. These share all basic properties with the usual maximally CHSH-violating correlations. These patches are separated by cubic surfaces of non-exposed extreme points. We provide a trigonometric parametrization of all extreme points, along with their exposing Tsirelson inequalities and quantum models. All non-classical extreme points (exposed or not) are self-testing, i.e., realized by an essentially unique quantum model. Two principles, which are specific to the minimal scenario, allow a quick and complete overview: The first is the pushout transformation, the application of the sine function to each coordinate. This transforms the classical polytope exactly into the correlation body $\mathcal{Q}$, also identifying the boundary structures. The second principle, self-duality, reveals the polar dual, i.e., the set of all Tsirelson inequalities satisfied by all quantum correlations. The convex body $\mathcal{Q}$ includes the classical correlations, a cross polytope, and is contained in the no-signaling body, a 4-cube. These polytopes are dual to each other, and the linear transformation realizing this duality also identifies $\mathcal{Q}$ with its dual.Comment: We also discuss the sets of correlations achieved with fixed Hilbert space dimension, fixed state or fixed observable

Stima speditiva degli scenari di danno sismico atteso per edifici in muratura mediante l’utilizzo di curve di Probit

Nel presente lavoro si presentano le curve di vulnerabilità degli edifici in muratura ricavate dall’analisi dei dati del terremoto del Friuli del 1976. In particolare le curve sono ricavate tramite l’analisi di Probit, una tecnica statistica largamente in uso nel campo delle analisi di rischio industriale e più in generale nei settori in cui si studiano fenomeni governati da una legge dose-effetto di tipo sigmoidale. Nell’articolo si mostra come tali curve possono essere direttamente impiegate per valutazioni previsionali di danno atteso su scala territoriale in quanto consentono di ricavare in modo relativamente semplice e rapido la percentuale di edifici che, sottoposti ad una determinata azione sismica, subiscono un determinato livello di danno strutturale espresso nella scala EMS-98. Nel lavoro si propone inoltre una metodologia di stima più ampia dello “scenario di danno”, basata sull’uso di una matrice di correlazione che lega l’indice di danno EMS-98 agli effetti indiretti in termini di giudizio di agibilità, riparabilità e probabilità di vittime associate. Tale matrice, anch’essa messa a punto sulla base dei dati del terremoto del Friuli, è stata validata e calibrata sui dati dalle schede AeDES compilate in occasione del terremoto Umbria-Marche

Anti-fibroblast antibodies detected by cell-based ELISA in systemic sclerosis enhance the collagenolytic activity and matrix metalloproteinase-1 production in dermal fibroblasts

Objectives. Antibodies binding to the surface of fibroblasts (anti-fibroblast antibodies: AFA) have been described in systemic sclerosis (SSc). We aimed to assess the effect of AFA on extracellular matrix (ECM) turnover and whether AFA were associated with anti-topoisomerase-I antibody. Methods. IgG were purified from AFA-positive and AFA-negative sera selected within 20 SSc and 20 healthy individuals, and tested on normal dermal fibroblasts, at protein and mRNA level, for their capacity to induce collagen deposition or degradation. Results. Fibroblasts stimulated with AFA-positive but not with AFA-negative and control IgG showed an increased capacity to digest collagen matrix and produce metalloproteinase-1 (MMP-1) while their production of total collagen, type I collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) was unaffected. The steady-state mRNA levels of MMP-1, COL1A1 and TIMP-1 paralleled the protein levels. AFA-positive IgG did not induce Smad 2/3 phosphorylation, indicating that this transforming growth factor-β signalling pathway was not involved. IL-1 and tumour necrosis factor (TNF) neutralization did not reverse the enhanced production of MMP-1, suggesting a direct effect of AFA on fibroblasts. Finally, anti-topoisomerase-I antibodies were present in 11 of 12 AFA-negative IgG, and an anti-topoisomerase-I monoclonal antibody failed to enhance MMP-1 production, thus indicating a lack of correlation between AFA and anti-topoisomerase-I antibody. Conclusions. These results indicate that SSc antibodies binding to fibroblasts enhance matrix degradation and MMP production events that may favour inflammation but do not directly impact on fibrosis developmen

The role of environmental estrogens and autoimmunity

The prevalence of autoimmune diseases has significantly increased over the recent years. It has been proposed that this epidemiological evidence could be in part attributable to environmental estrogens, compounds that display estrogen-like activity and are ubiquitously present in the environment. Environmental estrogens can be found in a wide variety of foods: phytoestrogens occur in plants such as clover and soy, while mycoestrogens are food contaminants produced by fungi. Meat, eggs and dairy products from animals given exogenous hormones contain relatively high concentration of estrogens. Among xenoestrogens, industrial estrogens are synthetic chemicals produced for specific purposes (pesticides, plastics, surfactants and detergents) while metalloestrogens are found in heavy metals. Estrogens can be also administered through medications (contraceptive pill, hormone replacement therapy, genistein, cimetidine, creams). There is a considerable burden of evidence in vitro and in animal models that these compounds may exert immunotoxic effects. However, to date there is no convincing data that exposure to environmental estrogens can be regarded as a risk for human health. In particular, there is no consensus whether prolonged exposure to relatively low concentrations of different estrogenic chemicals can affect the human immune system and induce clinically evident diseases in real-life scenario. Moreover, the effects on human health of the synergistic interactions between natural, medical, dietary and environmental estrogens have not been fully elucidated yet. Here we provide an extensive review of the in vivo and in vitro effects of environmental estrogens on the immune system, focusing on the evidences of association between exposure and autoimmune disorders

Mir-101-3p downregulation promotes fibrogenesis by facilitating hepatic stellate cell transdifferentiation during insulin resistance

Insulin resistance (IR) and microRNAs (miRNAs), which regulate cell-to-cell communication between hepatocytes and hepatic stellate cells (HSCs), may intertwine in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The aim of this study was to evaluate whether epigenetics and environmental factors interact to promote progressive NAFLD during IR. We examined the miRNA signature in insulin receptor haploinsufficient (InsR+/ 12) and wild-type (wt) HSCs by RNAseq (n = 4 per group). Then, we evaluated their impact in an IR-NASH (nonalcoholic steatohepatitis) model (InsR+/ 12 mice fed standard or methionine choline deficient (MCD) diet, n = 10 per group) and in vitro. InsR+/ 12 HSCs displayed 36 differentially expressed miRNAs (p < 0.05 vs. wt), whose expression was then analyzed in the liver of InsR+/ 12 mice fed an MCD diet. We found that miR-101-3p negatively associated with both InsR+/ 12 genotype and MCD (p < 0.05) and the histological spectrum of liver damage (p < 0.01). miR-101-3p was reduced in InsR+/ 12 hepatocytes and HSCs and even more in InsR+/ 12 cells exposed to insulin (0.33 \ub5M) and fatty acids (0.25 mM), resembling the IR-NASH model. Conversely, insulin induced miR-101-3p expression in wt cells but not in InsR+/ 12 ones (p < 0.05). In conclusion, IR combined with diet-induced liver injury favors miR-101-3p downregulation, which may promote progressive NAFLD through HSC and hepatocyte transdifferentiation and proliferation